Summary of Research Project:

Our goal is to find novel ways to treat pulmonary arterial hypertension (PAH). The approach we are pursuing is to increase signaling through the bone morphogenetic protein receptor (BMPR)-2.

Seventy percent of patients with familial and 20% of patients with idiopathic pulmonary arterial hypertension (IPAH) carry a mutation in one of the two BMPR2 alleles that leads to a dysfunctional signaling via this receptor. However, the penetrance i.e., the propensity of individuals with a mutation, to develop PAH is less than 20%. Recent studies have shown that reduced levels of the normal BMPR2 allele distinguish affected from non-affected family members. Even PAH associated with other diseases (APAH) can be accompanied by reduced protein expression of BMPR2. Therefore it seems that the level of signaling through the BMPR2 receptor is important in PAH. A novel approach to the prevention and treatment of pulmonary hypertension could be restoration of BMPR2 signaling.

We are pursuing 2 strategies, the first of which will be to modulate the levels of relevant micro-RNAs that impact BMPR2 expression by using micro RNA mimics or antagomirs. As a second strategy, we are screening pharmacologically active compounds and small molecules that could enhance signaling from the BMPR2 receptor.

We have developed a High Throughput Screen using 3600 FDA approved drugs and pharmacologically active compounds. With this technique, i8/25/11n addition to “hits” that enhance BMP signaling, we can also identify molecules and drugs that inhibit signaling from the BMPR2 receptor and therefore could be harmful in IPAH patients and non-affected family members with already compromised BMPR2 expression. We have already identified one compound, the immunosuppressive drug FK-506 (Tacrolimus), as having the propensity to increase BMP signaling. We validated these findings in cell culture and animal models of experimental pulmonary hypertension. Low dose FK-506 prevents and reverses established pulmonary hypertension in 3 different animal models of pulmonary hypertension (mice, rats). Given that FK-506 is an FDA-approved drug with a known side-effect profile and given our observation that even a very low dose of FK-506 can activate BMPR2 signaling, this drug seems to be very promising to test in the clinical setting.

Our research is very translational in nature. We hope to identify more compounds that will increase BMPR2 signaling and to develop novel approaches such as the use of microRNAs to influence BMPR2 expression with the ultimate goal to find ways how to arrest and prevent the development of pulmonary arterial hypertension.

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